2. Academic Validation
  3. From Hit to Lead: Discovery of Novel Selective RIPK1 Inhibitor with Pyridoimidazole Scaffold for the Treatment of Autoimmune Diseases through Phenotypic Screening and Structural Optimization

From Hit to Lead: Discovery of Novel Selective RIPK1 Inhibitor with Pyridoimidazole Scaffold for the Treatment of Autoimmune Diseases through Phenotypic Screening and Structural Optimization

  • J Med Chem. 2026 Feb 12;69(3):3252-3288. doi: 10.1021/acs.jmedchem.5c03145.
Jihong Wan 1,  Xiao-Yu Xiong 2 3,  Zixiang Geng 4,  Benjun Yuan 5,  Youzhen Ma 6,  Yan Zhao 1,  Zhi Ying Dorothy Wong 1,  Xinyi Kang 1,  Rui Fan 1,  Delin Min 1,  Huanren Yan 1,  Yibo Chen 1,  Dong-Yi He 2,  Jian-Ping Zuo 3,  Han-Chen Xu 2,  Yang Ding 4,  Zhiyi Liu 4,  Zixin Hu 1,  Fuzhuo Li 1,  Nannan Sun 5,  Yongfang Zhao 4,  Ze-Min Lin 3 7,  Mei-Lin Tang 1
Affiliations

Affiliations

  • 1 Shanghai Pudong Hospital, Pharmacophenomics Laboratory, Human Phenome Institute, Department of Natural Medicine, School of Pharmaceutical Sciences, Fudan University, Shanghai 201203, China.
  • 2 Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai 200052, China.
  • 3 Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Shi's Center of Orthopedics and Traumatology, Shuguang Hospital, Institute of Traumatology and Orthopedics, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 5 School of Pharmaceutical Sciences, College of Chemistry, Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Zhengzhou University, Zhengzhou 450001, China.
  • 6 School of Life Sciences, Xuzhou Medical University, No. 209 Tongshan Road, Yunlong District, Xuzhou 221004, China.
  • 7 Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
PMID: 41628914 DOI: 10.1021/acs.jmedchem.5c03145
Abstract

Autoimmune diseases remain challenging to treat due to the limitations of TNFα-targeted biologics and the inefficacy of small molecules directly targeting TNFα. RIPK1, a central mediator of TNFα-driven inflammation and Necroptosis, offers a promising alternative therapeutic target. Using drug repurposing and phenotype-based high-content screening of 378 clinical-stage kinase inhibitors, TAK-117 (a PI3Kα Inhibitor) was identified as a RIPK1 hit compound with a novel pyridoimidazole scaffold. Guided by structure-based optimization and four iterative SAR cycles, WJH-C19 was developed, exhibiting >1000-fold increased RIPK1 potency (IC50 = 5.7 nM) and negligible PI3Kα activity (IC50 > 10 μM). Mechanistically, WJH-C19 suppressed the RIPK1/RIPK3/MLKL signaling axis, attenuating inflammatory responses. Oral administration of WJH-C19 achieved robust efficacy in DSS-induced colitis and CFA-induced arthritis models, with favorable pharmacokinetics and no observable toxicity. These results establish WJH-C19 as a potent lead and highlight the pyridoimidazole scaffold as a privileged chemotype for RIPK1-targeted drug discovery in autoimmune diseases.

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